**1. Introduction**

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with significant morbidity and mortality rates. Hydroxychloroquine remains the hallmark in the management of SLE, exerting beneficial effects not only in mild manifestations but also in serious organ involvement [1]. In 2011, belimumab, a monoclonal antibody antagonizing soluble B-lymphocyte stimulator protein (BLyS) became the first approved biologic treatment in SLE patients with active, extrarenal, seropositive disease [2]. A decade later, in 2021, the US Food and Drug Administration (FDA) approved anifrolumab, a monoclonal antibody antagonist of the type 1 interferon receptor for the treatment of adult patients with moderate to severe SLE who are receiving standard therapy [3].

Despite these advances, corticoid dependence and the high rates of relapse underscore the need for more efficient treatment strategies.

In this chapter, we will review current as well as emerging biological therapies in SLE and provide the mechanistic rationale behind their development (**Table 1**).


**Table 1.** *Keys to SLE pathogenesis [4–7].*

## **2. Steps to SLE pathogenesis**

The pathogenesis of SLE is elusive and multifactorial. Mutations in genes related to toll-like receptors and type 1 interferon (IFN) signaling pathways and apoptotic waste clearance epigenetic factors such as DNA methylation and environmental factors including ultraviolet light, hormones, and viruses contribute to its manifestation [4]. Over 100 genetic loci identified through genome-wide association studies (GWAS) are associated with SLE [5].

Defective clearance of apoptotic cells and the accumulation of apoptotic debris play a key role in SLE pathogenesis [6], by stimulating the production of IFNa and promotion of autoimmunity due to a breakdown of self-tolerance. Neutrophil extracellular traps released by dying neutrophils during a process called NETosis may serve as well as a source of autoantigens [7]. Another key to SLE pathogenesis is Toll-like receptors (TLRs). TLRs are expressed in multiple immune cells including dendritic cells, macrophages, B and T cells are also stimulated by nucleic acids contained in apoptotic cells [4] and inducing a strong type I IFN production and plasmacytoid dendritic cells' activation.

The amplification and maintenance of autoimmunity in SLE patients are driven by multiple immune reactants including immune complexes, type I IFN, and other cytokines including B- cell activating factor (BAFF or BLyS), the target of Belimumab. Loss of T and B cell tolerance, deficient regulatory T cells (Tregs), aberrant development of B cells leading to production of autoantibodies play also a central role in SLE pathogenesis.
